PROJECT SUMMARY/ABSTRACT Cigarette smoking remains the chief preventable cause of cardiovascular and pulmonary disease. While evidence-based treatments improve a smoker?s chances of quitting successfully, even with such treatments, the majority of smokers still fail to quit long-term in a given quit attempt. There is a clear need for more effective treatments. The proposed research would evaluate two treatment modifications that are designed to enhance the effectiveness of varenicline, an FDA-approved smoking cessation medication: 1) extending the duration of varenicline treatment; and 2) adding the nicotine mini-lozenge to varenicline to form a combined treatment. While existing data suggest that both modifications may substantially enhance varenicline effectiveness, neither has been adequately tested. The proposed research will use a 2X2 factorial design to randomize 1000 smokers to one of two levels of each of two factors: Duration (12- vs. 24-weeks of medication) and Adjuvant (varenicline + placebo lozenge vs. varenicline + nicotine mini-lozenge). Thus, smokers will receive either standard varenicline treatment (12 weeks of varenicline therapy) or 1 of 3 innovative, enhanced treatments: 12 weeks of varenicline + mini-lozenge, 24 weeks of extended treatment with varenicline only, or 24 weeks of extended treatment with varenicline + mini-lozenge. Analyses will reveal whether the Duration and Adjuvant modifications produce additive or interactive effects on smoking abstinence at 52 weeks postquit, the primary outcome. Also, planned comparisons will determine if any of the enhanced conditions is superior to standard varenicline therapy. The hypothesis is that 24-week duration and the mini-lozenge adjuvant will produce significant, additive main effects so that their combination (24-weeks of varenicline + mini-lozenge) produces higher abstinence rates at 52-weeks postquit than does standard 12-week varenicline treatment. Other outcomes include prolonged smoking abstinence, treatment cost-effectiveness, withdrawal suppression, and adverse events. In sum, this research is designed to produce an especially effective smoking cessation treatment that should increase the rate of pharmacologic intervention with smokers in healthcare, reduce smoking prevalence in patient populations, and reduce incidence of cardiovascular and pulmonary disease.